Epstein-Barr virus (EBV) the causative agent of heterophile-positive acute infectious monocleosis, is a successful pathogen in the human species, asymptomatically infecting most normal adult individuals. In spite of their potential for unlimited growth, B cells naturally infected with EBV only rarely give rise to lymphoproliferative disease in man. Credit for such successful restraint is attributable, primarily to T cell immunity. Severe T cell immunodeficiency, such as that occurring in AIDS and solid organ transplant recipients, can result in the uncontrolled expansion of B lymphocytes naturally infected with EBV and the development of lymphoproliferative disease. As many as 32% of solid organ transplant recipients may develop lymphoproliferative disease generally involving EBV-infected B cells. IL-6, a multifunctional cytokine produced by monocytes, fibroblasts, endothelial cells, and other cell types promotes growth of EBV-infected B cells, acting as an autocrine and/or paracrine growth factor. In addition, this cytokine has been shown to increase the tumorigenicity of EBV-immortalized B cells in athymic mice. In the present study, we examined the possibility that IL-6 may play a role in the development of EBV-positive lymphoproliferative disease in immunosuppressed solid organ transplant recipients. Serum/plasma IL-6 bioactivity was found to be abnormally elevated, albeit transiently, in 17 of 18 solid organ transplant recipients, with post-transplant lymphoproliferative disease (PTLD), with a mean maximal level of 196.7 U/ml. This represents a 16.4 increase above the normal mean (11.3 U/ml). In contrast, only 3 of 10 solid organ transplant recipients with uncomplicated courses posttransplant had abnormally elevated serum/plasma IL-6 bioactivity (mean maximal level 41.4 U/ml, P = 0.0007). When transferred to single cell culture, the 11 PTLD tissues produced 640 to 1.25~10/6 IL-6 U/ml in the culture supernatant, with a mean maximal level of 35,025 IL-6 U/ml. Cell separation experiments demonstrated that the adherent cells, identified as non-B cells, were the principal source of IL-6 production in vitro by PTLD tissue. Control cultures of inflammatory lymphoid tissue negative for lymphoproliferative disease as well as of PBL from patients with acute EBV-induced infectious mononucleosis consistently produced<10 IL-6 U/ml. Thus, IL-6 is produced at high levels by PTLD tissues and may play a critical role in the pathogenesis of PTLD.